Pancreatic cancer is alone among the major cancers in its increasing prevalence, and it is predicted to be the second-leading cause of cancer death by 2030. A strategy to help reverse this trend is to identify and treat more pancreatic cancers at an early stage of the disease, when surgery and therapeutics are most effective. Currently no biomarker is good enough to be used for the detection of early-stage disease in people at elevated risk for pancreatic cancer. In our preliminary research, we have developed biomarkers a) that have better sensitivity and specificity for early-stage cancer than the current best biomarker for pancreatic cancer, CA 19-9, and b) that can detect cancers that are low in CA 19-9. The several individual biomarkers complement each other because each is elevated in distinct groups of patients. These encouraging results lead us to propose that a biomarker panel developed from these and related biomarkers will provide the necessary performance to enable clinical detection and diagnosis of early-stage pancreatic cancer. A second strategy for improving outcomes is to better identify those early-stage cancers that will rapidly progress. Some cancers that appear to be early-stage and resectable show progression within a short time after surgery. Biomarkers to identify such cancers would allow better treatment for those patients, as they could be spared the risk and recovery time of surgery and immediately begin the appropriate systemic treatment, likely leading to better results. Currently, we have no accurate indicators of rapid progression after surgery. One of the biomarkers discovered in our preliminary research is elevated in most patients who have rapid progression after surgery, suggesting the possibility of its use as a progression biomarker. Our goal is to develop biomarkers that will be effective for detecting early-stage pancreatic cancer (Aim 1) and for identifying the early-stage cancers that will rapidly progress (Aim 2). We will pursue this goal by optimizing the existing biomarkers and bolstering them with additional biomarkers, and by developing, testing, and validating panels of biomarkers that improve performance over the individual biomarkers. We hypothesize that the biomarker panels can achieve the performance required for further clinical validation. We are in a good position to achieve our goal, given the promising biomarkers already discovered and the convergence of all the other factors necessary for a successful project: we have assembled a team of top experts in the clinical, technological, and statistical fields, plus we have the sample resources, patient base, experimental methods, institutional environment and support, and passion as a team to deliver high-impact results.